Multifunctional hydrogel material as well as preparation method and application thereof

Abstract

The invention provides a multifunctional hydrogel material as well as a preparation method and application thereof, and relates to the technical field of biomedical materials. The multifunctional hydrogel material provided by the invention is mainly prepared from a hydroxyl-containing natural polymer material and butanediol diglycidyl ether through a cross-linking reaction. The multifunctional hydrogel material is good in stability, high in crosslinking degree, excellent in biocompatibility and low in immunogenicity, and the problems that a traditional crosslinking agent and a traditional crosslinking hydrogel material are poor in biocompatibility, large in inflammatory response and the like are solved while the mechanical property of the target hydrogel material is guaranteed. The preparation method of the multifunctional hydrogel material provided by the invention is simple and convenient, the purity of the hydrogel is improved, and the simplicity and rapidness of preparation of the cross-linked hydrogel are improved. The prepared multifunctional hydrogel material can effectively promote cell growth and proliferation, and has wide application prospects in the fields of wound dressings, medical filling materials and the like.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedical materials, and in particular to a multifunctional hydrogel material and a preparation method and application thereof. Background Art

[0002] Hydrogel materials have good biocompatibility and degradability, and are widely used in medical fields such as wound dressings, medical filling materials, artificial corneas, artificial joints, and controlled drug release. Natural polymer hydrogels have the advantages of good biocompatibility, abundant sources, low cost, and biodegradability, which effectively expands the application prospects of hydrogel materials.

[0003] In order to maintain the mechanical properties of hydrogel materials, natural polymers need to be cross-linked to obtain target cross-linked hydrogel materials. Traditional cross-linking agents mainly include divinyl sulfone (DVS) and butanediol diglycidyl ether (BDDE), but due to the toxicity of cross-linking agents, there are risks such as poor biocompatibility and immune response after implantation in the body. Therefore, the development of new cross-linking agents with better biocompatibility and easy-to-regulate performance is expected to fundamentally overcome the defects of traditional cross-linking agents, thereby obtaining new functional hydrogel materials with excellent biocompatibility, low immunogenicity and the ability to promote cell proliferation.

[0004] In view of this, the present invention is proposed. Summary of the invention

[0005] The first object of the present invention is to provide a multifunctional hydrogel material to solve at least one of the above problems.

[0006] The second object of the present invention is to provide a method for preparing the multifunctional hydrogel material.

[0007] The third object of the present invention is to provide the use of the multifunctional hydrogel material in the preparation of wound dressings, injection filling materials or drug controlled release materials.

[0008] In a first aspect, the present invention provides a multifunctional hydrogel material, which is mainly prepared by cross-linking reaction of a natural polymer material containing hydroxyl groups and butanediol diglycidyl ether.

[0009] As a further technical solution, the natural polymer material containing hydroxyl groups includes at least one of hyaluronic acid, sodium alginate, chitin, starch or cellulose.

[0010] As a further technical solution, the raw material of the multifunctional hydrogel material further includes at least one of an amine compound or a functional polypeptide.

[0011] As a further technical solution, the amine compound includes at least one of ethylenediamine, butanediamine, lysine, glutamic acid, arginine, polylysine, chitosan, sulfonated chitosan, polyimide or aminoheparin.

[0012] As a further technical solution, the functional polypeptide includes at least one of EGF epidermal growth factor, bFGF basic fibroblast growth factor, VEGF vascular lining remodeling factor, TGF transforming growth factor or NGF neural growth factor.

[0013] In a second aspect, the present invention provides a method for preparing the multifunctional hydrogel material, comprising the following steps:

[0014] An aqueous solution of a natural polymer material containing hydroxyl groups is prepared, the pH of the solution is adjusted to 6-13, and then a crosslinking agent solution containing butanediol diglycidyl ether is added to carry out a crosslinking reaction to prepare a multifunctional hydrogel material.

[0015] As a further technical solution, the concentration of the natural polymer material containing hydroxyl groups in the aqueous solution of the natural polymer material containing hydroxyl groups is 0.01wt%-40wt%;

[0016] And / or, the concentration of butanediol diglycidyl ether in the cross-linking agent solution is 0.01 wt%-25 wt%.

[0017] As a further technical solution, the cross-linking agent solution also contains at least one of an amine compound or a functional polypeptide;

[0018] The amine compound includes at least one of ethylenediamine, butanediamine, lysine, glutamic acid, arginine, polylysine, chitosan, sulfonated chitosan, polyimide or aminoheparin; the concentration of the amine compound in the crosslinking agent solution is 10wt%-20wt%;

[0019] The functional polypeptide comprises at least one of EGF epidermal growth factor, bFGF basic fibroblast growth factor, VEGF vascular lining remodeling factor, TGF transforming growth factor or NGF neural growth factor; the concentration of the functional polypeptide in the crosslinking agent solution is 0.05wt%-1wt%.

[0020] As a further technical solution, the temperature of the cross-linking reaction is 20-70°C;

[0021] The cross-linking reaction time is 24-72 hours.

[0022] In a third aspect, the present invention provides the use of the multifunctional hydrogel material in preparing wound dressings, injectable filling materials or drug controlled release materials.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] 1. The multifunctional hydrogel material obtained by the present invention has good stability, a high degree of cross-linking, excellent biocompatibility and low immunogenicity. While ensuring the mechanical properties of the target hydrogel material, it solves the problems of poor biocompatibility and large inflammatory response existing in traditional cross-linking agents and cross-linked hydrogel materials.

[0025] 2. The hydrogel cross-linking treatment method provided by the present invention avoids the cumbersome and time-consuming dialysis process in traditional cross-linking treatment, improves the purity of the hydrogel, and increases the simplicity and speed of cross-linked hydrogel preparation.

[0026] 3. The multifunctional hydrogel material obtained by the present invention contains functional polypeptide molecules that promote cell proliferation, which can effectively promote cell growth and proliferation, and has broad application prospects in the fields of wound dressings, medical filling materials, etc. DETAILED DESCRIPTION

[0027] The embodiments of the present invention will be described in detail below in conjunction with the embodiments and examples, but it will be appreciated by those skilled in the art that the following embodiments and examples are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work are within the scope of protection of the present invention. If specific conditions are not specified, proceed according to normal conditions or conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0028] In a first aspect, the present invention provides a multifunctional hydrogel material, which is mainly prepared by cross-linking reaction of a natural polymer material containing hydroxyl groups and butanediol diglycidyl ether.

[0029] The present invention provides a multifunctional hydrogel material with good stability, high degree of cross-linking, excellent biocompatibility and low immunogenicity. While ensuring the mechanical properties of the target hydrogel material, it solves the problems of poor biocompatibility and large inflammatory response existing in traditional cross-linking agents and cross-linked hydrogel materials.

[0030] In some optional embodiments, the natural polymer material containing hydroxyl groups includes but is not limited to at least one of hyaluronic acid, sodium alginate, chitin, starch or cellulose, or other natural polymer materials containing hydroxyl groups known to those skilled in the art.

[0031] In some optional embodiments, the raw material of the multifunctional hydrogel material further includes at least one of an amine compound or a functional polypeptide.

[0032] The amine compounds include but are not limited to at least one of ethylenediamine, butanediamine, lysine, glutamic acid, arginine, polylysine, chitosan, sulfonated chitosan, polyimide or aminoheparin, or other amine compounds known to those skilled in the art.

[0033] In some optional embodiments, the functional polypeptide includes but is not limited to at least one of EGF epidermal growth factor, bFGF basic fibroblast growth factor, VEGF vascular lining remodeling factor, TGF transforming growth factor or NGF neural growth factor, or other functional polypeptides known to those skilled in the art.

[0034] In a second aspect, the present invention provides a method for preparing the multifunctional hydrogel material, comprising the following steps:

[0035] An aqueous solution of a natural polymer material containing hydroxyl groups is prepared, the pH of the solution is adjusted to 6-13, and then a crosslinking agent solution containing butanediol diglycidyl ether is added to carry out a crosslinking reaction to prepare a multifunctional hydrogel material.

[0036] The preparation method of the multifunctional hydrogel material provided by the present invention avoids the cumbersome and time-consuming dialysis process in the traditional cross-linking treatment, improves the purity of the hydrogel, and increases the simplicity and quickness of the preparation of the cross-linked hydrogel.

[0037] In some optional embodiments, the concentration of the natural polymer material containing hydroxyl groups in the aqueous solution of the natural polymer material containing hydroxyl groups may be, for example, but not limited to, 0.01wt%, 0.05wt%, 0.1wt%, 0.5wt%, 1wt%, 5wt%, 10wt%, 20wt% or 40wt%;

[0038] In some optional embodiments, the concentration of butanediol diglycidyl ether in the cross-linking agent solution may be, for example, but not limited to, 0.01 wt%, 0.05 wt%, 0.1 wt%, 0.5 wt%, 1 wt%, 5 wt%, 10 wt%, 20 wt% or 25 wt%.

[0039] By further optimizing and adjusting the concentration of natural polymer materials containing hydroxyl groups and butanediol diglycidyl ether, the performance of the prepared hydrogel is improved.

[0040] In some optional embodiments, the cross-linking agent solution further contains at least one of an amine compound or a functional polypeptide;

[0041] The amine compound includes but is not limited to at least one of ethylenediamine, butanediamine, lysine, glutamic acid, arginine, polylysine, chitosan, sulfonated chitosan, polyimide or aminoheparin, or other amine compounds known to those skilled in the art.

[0042] The concentration of the amine compound in the cross-linking agent solution may be, for example, but not limited to, 10 wt %, 12 wt %, 14 wt %, 16 wt %, 18 wt % or 20 wt %.

[0043] The functional polypeptides include but are not limited to at least one of EGF epidermal growth factor, bFGF basic fibroblast growth factor, VEGF vascular lining remodeling factor, TGF transforming growth factor or NGF neural growth factor, or other functional polypeptides known to those skilled in the art.

[0044] The concentration of the functional polypeptide in the cross-linking agent solution may be, for example, but not limited to, 0.05 wt%, 0.1 wt%, 0.5 wt% or 1 wt%.

[0045] In some optional embodiments, the total mass concentration of the cross-linking agent solution may be, for example, but not limited to, 1 wt%, 5 wt%, 10 wt%, 20 wt% or 40 wt%.

[0046] In some optional embodiments, the pH of the aqueous solution of the natural polymer material containing hydroxyl groups is adjusted to 7-13.

[0047] In some optional embodiments, the temperature of the cross-linking reaction may be, for example, but not limited to, 20°C, 30°C, 40°C, 50°C, 60°C or 70°C;

[0048] The cross-linking reaction time may be, for example, but not limited to, 24 hours, 36 hours, 48 ​​hours, 60 hours or 72 hours.

[0049] In some optional embodiments, the cross-linking reaction is carried out under shaking conditions.

[0050] By further optimizing and adjusting the cross-linking reaction conditions, the performance of the prepared multifunctional hydrogel material is improved.

[0051] In some optional embodiments, after the cross-linking reaction is completed, the mixture is washed with deionized water and then stored in a PBS solution at 4°C.

[0052] In a third aspect, the present invention provides the use of the multifunctional hydrogel material in preparing wound dressings, injectable filling materials or drug controlled release materials.

[0053] The multifunctional hydrogel material obtained by the present invention contains functional polypeptide molecules that promote cell proliferation, can effectively promote cell growth and proliferation, and has broad application prospects in the fields of wound dressings, medical filling materials, etc.

[0054] The present invention is further described below by means of specific examples. However, it should be understood that these examples are only used for more detailed description and should not be construed as limiting the present invention in any form.

[0055] Example 1

[0056] Dissolve 5 g of sodium alginate in 10 ml of deionized water, add functional crosslinkers in batches at 70°C, and shake for 24 hours. The total mass concentration of the multifunctional crosslinker is 1%. After the reaction, shake and wash with deionized water. The resulting material is the target hydrogel material and is stored in PBS solution at 4°C.

[0057] The multifunctional cross-linking agent contains 0.1% of functional polypeptide and 0.9% of butanediol diglycidyl ether.

[0058] Example 2

[0059] Dissolve 5 g of hyaluronic acid in 10 ml of deionized water, add functional crosslinkers in batches at 37°C, and shake for 24 hours. The total mass concentration of the multifunctional crosslinker is 5%. After the reaction, shake and wash with deionized water. The resulting material is the target hydrogel material and is stored in PBS solution at 4°C.

[0060] The multifunctional cross-linking agent contains 1% of functional polypeptide and 4% of butanediol diglycidyl ether.

[0061] Example 3

[0062] Dissolve 5 g of hyaluronic acid in 10 ml of deionized water, add functional crosslinkers in batches at room temperature, and shake for 36 hours. The total mass concentration of the multifunctional crosslinker is 13%. After the reaction, wash with deionized water. The resulting material is the target hydrogel material and is stored in PBS solution at 4°C.

[0063] The multifunctional cross-linking agent contains 1% of functional polypeptide and 12% of butanediol diglycidyl ether.

[0064] Example 4

[0065] Dissolve 20g of hyaluronic acid in 50ml of deionized water, add functional crosslinker in batches at room temperature, and shake for 48 hours. The total mass concentration of the multifunctional crosslinker is 20%. After the reaction, shake and wash with deionized water. The obtained material is the target hydrogel material, which is stored in PBS solution at 4°C.

[0066] The multifunctional cross-linking agent contains 10% of amine compounds, 1% of functional polypeptides and 9% of butanediol diglycidyl ether.

[0067] Example 5

[0068] Dissolve 20g of hyaluronic acid in 50ml of deionized water, add functional crosslinker in batches at 37℃, and shake for 36 hours. The total mass concentration of multifunctional crosslinker is 15%. After the reaction, shake and wash with deionized water. The obtained material is the target hydrogel material, which is stored in PBS solution at 4℃.

[0069] The multifunctional cross-linking agent contains 10% of amine compounds, 1% of functional polypeptides and 4% of butanediol diglycidyl ether.

[0070] Example 6

[0071] Dissolve 20g of hyaluronic acid in 50ml of deionized water, add functional crosslinker in batches at 70℃, and shake for crosslinking reaction for 36 hours. The total mass concentration of multifunctional crosslinker is 5%. After the reaction, shake and wash with deionized water. The obtained material is the target hydrogel material, which is stored in PBS solution at 4℃.

[0072] The multifunctional cross-linking agent contains 1% of functional polypeptide and 4% of butanediol diglycidyl ether.

[0073] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein by equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A multifunctional hydrogel material, characterized in that: It is mainly prepared by cross-linking reaction of natural polymer materials containing hydroxyl groups and butanediol diglycidyl ether.

2. The multifunctional hydrogel material according to claim 1, characterized in that: The natural polymer material containing hydroxyl groups includes at least one of hyaluronic acid, sodium alginate, chitin, starch or cellulose.

3. The multifunctional hydrogel material according to claim 1, characterized in that: The raw materials of the multifunctional hydrogel material also include at least one of amine compounds or functional polypeptides.

4. The multifunctional hydrogel material according to claim 3, characterized in that: The amine compound includes at least one of ethylenediamine, butanediamine, lysine, glutamic acid, arginine, polylysine, chitosan, sulfonated chitosan, polyimide or aminoheparin.

5. The multifunctional hydrogel material according to claim 3, characterized in that: The functional polypeptide includes at least one of EGF epidermal growth factor, bFGF basic fibroblast growth factor, VEGF vascular lining remodeling factor, TGF transforming growth factor or NGF neural cell growth factor.

6. The method for preparing the multifunctional hydrogel material according to any one of claims 1 to 5, characterized in that: The following steps are involved: An aqueous solution of a natural polymer material containing hydroxyl groups is prepared, the pH of the solution is adjusted to 6-13, and then a crosslinking agent solution containing butanediol diglycidyl ether is added to carry out a crosslinking reaction to prepare a multifunctional hydrogel material.

7. The preparation method according to claim 6, characterized in that: The concentration of the natural polymer material containing hydroxyl groups in the aqueous solution of the natural polymer material containing hydroxyl groups is 0.01wt%-40wt%; And / or, the concentration of butanediol diglycidyl ether in the cross-linking agent solution is 0.01 wt%-25 wt%.

8. The preparation method according to claim 6, characterized in that: The cross-linking agent solution also contains at least one of an amine compound or a functional polypeptide; The amine compound includes at least one of ethylenediamine, butanediamine, lysine, glutamic acid, arginine, polylysine, chitosan, sulfonated chitosan, polyimide or aminoheparin; the concentration of the amine compound in the crosslinking agent solution is 10wt%-20wt%; The functional polypeptide comprises at least one of EGF epidermal growth factor, bFGF basic fibroblast growth factor, VEGF vascular lining remodeling factor, TGF transforming growth factor or NGF neural growth factor; the concentration of the functional polypeptide in the crosslinking agent solution is 0.05wt%-1wt%.

9. The preparation method according to claim 6, characterized in that: The temperature of the cross-linking reaction is 20-70°C; The cross-linking reaction time is 24-72 hours.

10. Use of the multifunctional hydrogel material according to any one of claims 1 to 5 in preparing wound dressings, injection filling materials or drug controlled release materials.